Sunday, May 18, 2025
5/18/2025
Structure, Function, and Mechanism of Zinc ABC Transporters in Bacteria - ABSTRACT Our research laboratory focuses on elucidating the structure, function, and mechanism of bacterial proteins with relevance to human health. We use a wide array of biophysical, structural, and genetic techniques to accomplish this. The current work is dedicated to investigating bacterial ATP-binding cassette (ABC) transporters of the essential metal zinc. These are critical for virulence in many pathogenic bacteria and differ significantly from zinc transporters in mammals, making them attractive targets for the development of novel antibiotics. Achieving our research goals for the next five years will make important progress toward understanding how these systems may be exploited to treat bacterial infections, particularly for those species that have become resistant to our current arsenal of antibiotics. These goals include determining the first high-resolution structures of intact zinc ABC transporter systems from two divergent families, namely ZnuABC and ZrgABCDE. The latter system was only recently discovered, and virtually nothing is known about how it functions. Both systems are prevalent in human pathogens including multidrug resistant organisms. We will also initiate a rigorous assessment of the role of internal dynamics in the interaction between transporter components and subsequent delivery of zinc using nuclear magnetic resonance (NMR) and fluorescence spectroscopy techniques among others. These experiments provide important complementary information on protein motions to the static, high-resolution structural data available from crystal structures and cryo-EM. Finally, we will confirm the functions of various zinc transporter components in vivo and in vitro by generating genetic mutations in relevant species and developing zinc transport assays in proteoliposomes, respectively. Toward the end of the five-year project period, we will have amassed sufficient structural information to begin the rational development of compounds to inhibit bacterial zinc transport as novel antibiotics. The overarching goal of our research lab is to use structural information to provide new weapons in the fight against antibiotic resistant bacteria, which pose a significant and growing threat.
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